DOSE INTENSITY OF INDUCTION CHEMOTHERAPY IN PEDIATRIC ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract

Objective: This study compares the dose intensity of induction regimens by evaluating outcomes such as early deaths, death in the first remission, and survival. The results of this study will contribute to the development of therapeutic protocols with a reasonable balance in the intensity of induction, allowing remission to be achieved with less toxicity, adapting and establishing the treatment for acute childhood myeloid leukemia in developing countries. Methods: Pubmed and Scopus were used for systematic searches performed in January 2021. Descriptors involving specific or synonymic words such as Acute myeloid leukemia, pediatric, induction, and dose-intensity combined with Boolean operators AND and OR were used, without limits of time-frame or language. All relevant studies were read in full, and the data extraction was performed for those that fulfilled the inclusion criteria (patients aged between 0–21 years old, diagnosed with AML, describing results of induction regimens where one of the groups – intervention or comparison –included different dosing for the same chemotherapy drug). Were excluded the studies publishing exclusively Down's Syndrome patients and acute promyelocytic leukemia diagnosis, single-arm studies (with no comparator group), and studies where the intervention group had a different chemotherapy regimen than the comparator group. Results: The initial search retrieved 1185 papers. In the second round of screening of the remaining 207 articles, full-text papers were assessed for eligibility. From the nine papers included with dose modification during the induction phase of chemotherapy treatment, six referred to changes on cytarabine (ARA-C), two on idarubicin (IDR), and two on daunorubicin (DNR) (one of these studies simultaneously changed ARA-C and DNR). Results showed no significant difference between standard vs. high doses for CR and death during induction. Relapse rates were higher in the standard-dose than in the high-dose arms (1.44; 95% IC: 1.22–1.69). Despite the higher risk of relapse in the standard-dose group, event-free survival analysis shows no significant difference between the arms of each study. Discussion: The outcome of AML treatment in children and adolescents has improved over the last decades. Overall survival rates are now superior to 70% due to implementing strategies such as intensification of therapy, refinements in supportive care, and more precise risk classification. However, treatment-related deaths are exceptionally high in places with limited resources. Even regimens with standard-dose chemotherapy are associated with life-threatening complications due to profound myelosuppression and organ dysfunction. Establishing the best combination and sequence of treatment components, including hematopoietic stem cell transplantation, remains an unmet need. Conclusion: There is no significant difference between standard vs. high doses of chemotherapy during induction for selected outcomes such as complete remission and event-free survival. Reducing the dose intensity of standard AML remission induction regimens should be investigated in regions with limited resources.